Regulation of Intestinal Electroneutral Sodium Absorption and the Brush Border Na+/H+ Exchanger (NHE3) by Intracellular Calcium

摘要

Intestinal electroneutral Na⁺ absorptive processes account for most intestinal Na⁺ absorption in the period between meals and also for the great majority of the increase in ileal Na⁺ absorption that occurs post-prandially. In most diarrheal diseases, there is inhibition of neutral NaCl absorption. Elevated levels of intracellular calcium ([Ca²⁺]i) are known to inhibit NaCl absorption and involve multiple components of the Ca²⁺ signaling pathway. The BB Na⁺/H⁺ exchanger NHE3 accounts for most of the recognized digestive changes in neutral NaCl absorption, as well as most of the changes in Na⁺ absorption that occur in diarrheal diseases. Previous studies have examined several aspects of Ca²⁺ regulation of NHE3 activity. These include phosphorylation, protein trafficking and multi-protein complex formation. In addition, recent studies have demonstrated the role of the NHERF family of PDZ domain–containing proteins in Ca²⁺ regulation of NHE3 activity, thereby adding a new level of complexity to understanding Ca²⁺-dependent inhibition of Na⁺ absorption. In this article, we will review the current understanding of (1) Ca²⁺ signaling events in intestinal epithelial cells; (2) Ca²⁺ regulation of intestinal electroneutral sodium absorption, which includes NHE3; and (3) the role of the NHERF family of PDZ domain–containing proteins in Ca²⁺ regulation of NHE3 activity. We will also present new data on using advanced imaging showing rapid BB NHE3 endocytosis in response to elevated [Ca²⁺]i.